Of the estimated 1 million cases of breast cancer diagnosed worldwide in 2008, it is estimated that 172,695 harbored the triple-negative phenotype. Triple-negative breast cancer is currently receiving a tremendous and appropriate amount of research attention given its unique biology, overall poor prognosis, aggressive and early pattern of metastases and relative lack of therapeutic targets when compared with endocrine-sensitive and HERK-2 positive breast cancers. There is a clear need to increase the number of chemotherapeutic options for this and other types of breast cancer.
Metallo-drugs are important tools in current cancer therapy. Platinum-derived drugs are commonly used, particularly for the treatment of testicular and ovarian cancers, but have failed in breast cancers. In addition, the toxicity of Pt derivatives has prompted the search for alternative metallo-drugs. In the search for metal-based chemotherapeutics with improved properties with respect to platinum-based drugs used in the clinic, ruthenium compounds have emerged as promising candidates.
Ruthenium complexes have certain characteristics which make them attractive as potential chemotherapeutics for different diseases. Ruthenium metal compounds can easily access multiple oxidation states (II, III and possibly IV) in biological fluids. Ruthenium (III) compounds could potentially behave as pro-drugs as they can be reduced to ruthenium (II) derivatives in solid tumor masses where the high content in oxygen may act as a reducing environment. As platinum-based drugs, ruthenium compounds can exchange N and O-donor molecules with the added advantage of the possibility of forming octahedral complexes (of interest in reactions with DNA). Ruthenium derivatives probably use transferrin to accumulate into tumors due to the similarities with iron. The lower toxicity when compared to cisplatin and platinum based compounds of ruthenium compounds and their cytotoxic and/or antimestastatic properties has resulted in two ruthenium(III) compounds (NAMI-A and KP1019) having entered clinical trials (phase I and II). These compounds are about to be commercialized as a second line therapy in combination with gemcitabine in the treatment of NSCLC (NAMI-A) and for colorectal cancer (KP1019).
While the use of ruthenium-based chemotherapeutic have proven successful for some forms cancer, there is still a desire for different chemotherapeutics and particularly chemotherapeutics useful against triple negative breast cancer.